Differential control of gene expression is essential to the growth and development of all multicellular organisms. Although gene expression can be controlled at many steps along the path from DNA to protein, the major control point for most genes is at the initiation of transcription. This critical step is regulated both positively and negatively by a combination of general and tissue specific transcription factors, the majority of which function to stimulate transcription of one or more target genes.
Many transcription factors are modular proteins that contain separable DNA binding and transcriptional activation (or repression) domains. The DNA binding domain interacts with specific DNA sequences (control elements) near the promoter region of the gene; this interaction brings the activation(or repression) domain into a position where it can interact with other proteins to stimulate (or repress) transcription. Many transcription factors require dimerization or multimerization to be fully functional. For example, members of the helix-loop-helix family of transcription factors function as homo-/or hetero-dimers. The monomeric forms of these factors lack DNA binding activity. (Stryer, L. (1995) Biochemistry, 4th ed., pp 998-999.)
CCR4 is a general transcription factor in yeast that appears to be a component of a multisubunit complex. CCR4 stimulates the expression of numerous genes involved in non-fermentative growth. In particular, CCR4 is required for expression of the glucose-repressible alcohol dehydrogenase II gene (ADH2). Although CCR4 does not appear to bind DNA directly, when fused to the DNA binding domain of LexA, CCR4 can function as a glucose responsive transcriptional activator. CCR4 physically interacts with several other protein factors. Two of these CCR4 associated factors, CAF1 and CAF2, bind to a leucine rich repeat motif in the middle of the CCR4 protein. (Denis, C. L. and Malvar, T. (1990) Genetics 124: 283-291; Malvaret al. (1992) Genetics 132 (4):951-962; Draper, M. P. et al. (1994) Mol. Cell. Biol. 14(7): 4522-4531; and Draper, M. P. et al. (1995) Mol. Cell. Biol. 15(7): 3487-3495.)
CAF1 is an evolutionarily conserved mouse protein, with homologs identified in human, S. cerevisiae, C. elegans, and A. thaliana. A yeast homolog of CAF1, POP2, was first identified by its effects on glucose regulated gene expression. Consistent with a proposed function as a transcription factor, both mouse CAF1 and yeast CAF1 can activate transcription of a LexA responsive reporter gene when fused to the LexA DNA binding domain. In addition, CAF1 contains several structural features commonly found in transcription factors, e.g., a proline-rich region, several glutamine-rich regions, and a serine/threonine-rich region. (Sakai, A. et al. (1992) Nuc. Acids Res. 20: 6227-6233; Draper, M. P. et al. (1995) supra.)
A second CCR4 associated factor, CAF2, is a yeast protein kinase that was first identified as DBF2 and shown to be required for cell cycle progression. Immunoprecipitation and yeast two hybrid studies demonstrated that CCR4, CAF1, and CAF2 associate in vivo to form a stable complex. In addition, mutations in the genes encoding CCR4, CAF1, or CAF2 result in a similar set of pleiotropic phenotypes, including specific transcriptional defects and cell cycle progression defects. For example, mutations in any of the three genes can suppress the elevated expression of the ADH2 and HIS4-912 genes that occurs in spt6 and spt10 mutants. Taken together, the results suggest that CAF1, CAF2, and CCR4 function together as components of an evolutionarily conserved multi-protein complex that regulates transcription of numerous genes. (Draper, M. P. et al. (1995) supra.; Liu, H. Y., et al. (1997) EMBO J. 16(17):5289-5298.)
Defects in transcriptional regulation are known to contribute to oncogenesis, presumably through their affects on the expression of genes involved in cell proliferation. For example, mutant forms of transcription factors encoded by proto-oncogenes, e.g., Fos, Jun, Myc, Rel, and Spi1, may be oncogenic due to increased stimulation of cell proliferation. Conversely, mutant forms of transcription factors encoded by tumor suppressor genes, e.g., p53, RB1, and WT1, may be oncogenic due to decreased inhibition of cell proliferation. (Latchman, D. (1995) Gene Regulation: A Eukaryotic Perspective, 2nd ed. Chapman and Hall, London, UK, pp 242-255.)
The discovery of a new CAF1-related protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, and prevention disorders associated with cell proliferation and inflammation.